BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES

疟疾寄生虫中的生物能量学和质子泵

• 批准号: 6836481
• 负责人: AKHIL B VAIDYA
• 金额: $ 33.75万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836481
• 关键词: BIOENERGETICS; PROTON; PUMPS; MALARIA; PARASITES

EXCEED THE SPACE PROVIDED. Transport across the plasma membrane is a critical feature of all cellular physiology. Many gatekeepers at the plasma membrane are assisted by ionic and electric gradients across the membrane. Cells expend enormous energy-- up to 50% of intracellular ATP-- for maintenance of such electrochemical gradients. Energy economics of charging the plasma membrane with an electrochemical gradient for such transport remains virtually unknown in malaria parasites. The fact that erythrocytic stages of malaria parasites derive their ATP mainly through substrate-level phosphorylation, eking out a mere two ATP molecules per glucose molecule, must place significant constraints on parasite energy utilization. This project seeks to explore an alternate and/or adjunct energy source for malaria parasites. Recent evidence shows that Plasmodium species contains two members (PfVP1 and PfVP2) of the plant-like energy- conserving, membrane-associated H*-pumping pyrophosphatases. The vacuolar pyrophosphatases (V-PPases) of plants couple the energy generated by hydrolysis of the phosphoanhydride bond of inorganic pyrophosphate (PP_) to pump H ¿ across the vacuolar membrane. In malaria parasites, preliminary data suggest that the enzyme is located within the parasite plasma membrane. This location would suggest that H¿ translocation across the parasite plasma membrane could be energized through PP_ hydrolysis by the PPases in concert with ATP hydrolysis by the V-type ATPase. Because animal cells do not possess homologues of V-PPases, the presence of these enzymes in malaria parasites offers candidates for devising selectively toxic inhibitors. This project will undertake basic investigations on the biochemistry and cell biology of PfVP1 and PfVP2. Gene disruption approaches will be undertaken to assess contributions made by these molecules to the parasite physiology. The possibility that V-ATPase of malaria parasites may function work in reverse to synthesize ATP by using the proton motive force generated by the V-PPases under high energy demand will be explored. Furthermore, an unusual subunit configuration observed for the FoF1-ATP synthase of malaria parasites will be investigated to assess the contribution of this usually mitochondrial proton pumping complex to parasite physiology. Results from this project have a potential to require a major revision of our view of malaria parasite bioenergetics. Unique features of proton homeostasis and bioenergetics in malaria parasites likely to be uncovered in this project could form the basis for devising novel approaches to malaria control. PERFORMANCESITE( ========================================Section End===========================================

超出所提供的空间。跨质膜的运输是所有细胞生理学的一个关键特征。质膜上的许多看门人都受到跨膜离子和电场梯度的帮助，细胞消耗着高达细胞内 ATP 的 50% 的能量。 - 维持这种电化学梯度 在疟疾寄生虫的红细胞阶段，用电化学梯度对质膜进行充电的能源经济学实际上仍然未知。寄生虫主要通过底物水平磷酸化获得 ATP，每个葡萄糖分子仅产生两个 ATP 分子，这必然对寄生虫的能量利用产生重大限制。该项目旨在探索疟疾寄生虫的替代和/或辅助能源。显示疟原虫物种包含植物样能量保存、膜相关的 H* 泵送焦磷酸酶的两个成员（PfVP1 和 PfVP2）。植物的焦磷酸酶 (V-PPase) 将无机焦磷酸 (PP_) 的磷酸酐键水解产生的能量耦合到泵 H ¿在疟疾寄生虫中，初步数据表明该酶位于血浆寄生虫膜内。跨寄生虫质膜的易位可以通过 PPase 的 PP_ 水解以及 V 型 ATPase 的 ATP 水解来激发，因为动物细胞不具有 V-PPase 的同源物，所以疟疾寄生虫中这些酶的存在提供了候选者。该项目将对 PfVP1 和 PfVP2 的生物化学和细胞生物学进行基础研究，以评估基因破坏方法的贡献。疟疾寄生虫的 V-ATP 酶可能在高能量需求下利用 V-PP 酶产生的质子动力反向合成 ATP。此外，还将探讨一种不寻常的亚基结构。将研究观察到的疟疾寄生虫 FoF1-ATP 合酶，以评估这种通常为线粒体质子泵复合物对寄生虫生理学的贡献。该项目的结果有可能需要对我们对疟疾寄生虫的看法进行重大修改。该项目可能发现的疟疾寄生虫的质子稳态和生物能学的独特特征可以为设计疟疾控制新方法奠定基础。 =======================章节结束=============================================